CN108169399A - The separation method of impurity in ethyl demethylaminothiazolyloximate crude product - Google Patents
The separation method of impurity in ethyl demethylaminothiazolyloximate crude product Download PDFInfo
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- CN108169399A CN108169399A CN201711348703.3A CN201711348703A CN108169399A CN 108169399 A CN108169399 A CN 108169399A CN 201711348703 A CN201711348703 A CN 201711348703A CN 108169399 A CN108169399 A CN 108169399A
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- G—PHYSICS
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- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
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Abstract
The invention belongs to pharmaceutical chemistry analysis technical fields, are specifically related to a kind of separation method of impurity in ethyl demethylaminothiazolyloximate crude product.Ethyl demethylaminothiazolyloximate is measured with LC MS methods, one or more impurity in ethyl demethylaminothiazolyloximate are determined according to relative retention time and/or molecular weight；One or more impurity corresponding with relative retention time and/or molecular weight are enriched with using reverse phase silica gel column, further isolates and purifies, collects the relative retention time and/or a kind of corresponding impurity of molecular weight.Detection method is simple, result is accurate, is controlled suitable for the impurity analysis of cephalo-type sample.Separation and concentration ethyl demethylaminothiazolyloximate impurity is used in combination using LC MS methods and reverse phase silica gel column, the impurity rate of recovery reaches 5%~10%, and the purity of ethyl demethylaminothiazolyloximate is 96.5%~98%.
Description
Technical field
The invention belongs to pharmaceutical chemistry analysis technical fields, are specifically related to miscellaneous in a kind of ethyl demethylaminothiazolyloximate crude product
The separation method of matter.
Background technology
Ainothiazoly loximate is a kind of important medicine intermediate, and the 1980s, mid-term found that cefotaxime acid compounds close
Into cephalosporin there is the antibacterial activity that attracts people's attention, toxic side effect is small.Cefotaxime acid compounds are as antibiotic accordingly
Side chain receives favor.Ethyl demethylaminothiazolyloximate is mainly used for synthesizing cephalosporins medicine, is that cephalo removes first oxime, ceftriaxone, head
The important intermediate of the drugs such as his pyridine of spore.The synthesis technology of traditional ainothiazoly loximate can be divided by raw material difference：Acetoacetate first
Ester process, ethyl acetoac etate process, chloracetyl acetin method.Main several producers domestic at present are general mainly with acetoacetate
Ethyl ester prepares demethyl Ethyl Methylaminothiazolyloximate for starting material, and main production is following two：
It is starting material that one kind, which is ethyl acetoacetate, and nitrosation reaction is carried out under sulfuric acid catalysis, obtains 2- oximido second
Ethyl acetoacetic acid ethyl ester, then extracted with dichloromethane, chloroform equal solvent, extract liquor is subjected to halogenation, the thiocarbamide in alcohol-water system
Cyclization can obtain ethyl demethylaminothiazolyloximate.The technique carries out halogenating reaction again using first progress oximation reaction, since oximate is produced
Object is unstable, is decomposed during halogenation, causes reaction substrate sticky, and impurity increases, and difficulty is caused to isolating and purifying for product,
Yield is low.
Another kind carries out halogenation with bromine under cryogenic using ethyl acetoacetate as starting material, obtains halogen
For ethyl acetoacetate, which with sodium nitrite is reacted, thiocarbamide cyclization is used under alcohol water condition.The process route is because of second
Carbonyl active hydrogen number is more in ethyl acetoacetic acid ethyl ester, and polysubstituted reaction, product yield 45% or so easily occur for halogenation process.
Invention content
The purpose of the present invention is overcome the deficiencies of the prior art and provide impurity in a kind of ethyl demethylaminothiazolyloximate crude product
Separation method, the detection method is simple, result is accurate, is controlled suitable for the impurity analysis of cephalo-type sample.
The separation method of impurity, specifically includes following steps in ethyl demethylaminothiazolyloximate crude product of the present invention：
(1) ethyl demethylaminothiazolyloximate is measured with LC-MS methods, first is determined according to relative retention time and/or molecular weight
One or more impurity in Ethyl Methylaminothiazolyloximate；
(2) one or more impurity corresponding with relative retention time and/or molecular weight are enriched with using reverse phase silica gel column, into
One step isolates and purifies, and collects the relative retention time and/or a kind of corresponding impurity of molecular weight.
Wherein：
Flowing phase pH value is 2.00~5.00 used by LC-MS methods measure.
Mobile phase solvent is water-acetonitrile-methanol used by LC-MS methods measure, and buffer solution is potassium dihydrogen phosphate.
Comprising 30%~60% acetonitrile of mass fraction in mobile phase, 0.1%~0.6% potassium dihydrogen phosphate, water 20%~
25%, remaining as methanol.
In the detection of LC-MS methods the measuring conditions that use of HPLC for：Mobile phase solvent is water-acetonitrile-methanol mixed solution, is delayed
Fliud flushing is potassium dihydrogen phosphate；Column temperature is 20-40 DEG C；Flow velocity is 1-1.5ml/min；Detection wavelength is 245~260nm, preferably
254nm；Chromatographic column is stationary phase for octadecylsilane chemically bonded silica, 150 × 4.6 × 5um of model or 150mm × 4.6 ×
The stainless steel chromatographic column of 3.5um or 150mm × 2.1 × 5um.
ESI positive ion detections are used in interpretation of mass spectra；Scanning range is 100~3000m/z.
The gradient elution step of chromatographic column is when HPLC is measured：
(1) after sample is dissolved in methanol, wet method upper prop；
(2) pillar first is rinsed with the ethyl acetate 300ml of relatively low polarity, then successively with pure methanol solution 100ml, 80% first
Alcohol-water solution 300ml, 60% methanol-water solution 300ml, 40% methanol-water solution 300ml and 20% methanol-water solution
300ml is eluted；Each 4 batches of receptions of concentration gradient point, every batch of receive about 50ml；
(3) enrichment solution carries out HPLC detections.
By one mass spectrogram of Fig. 1 impurity it is found that ethyl demethylaminothiazolyloximate impurity of the present invention has the following structure formula：
By one mass spectrogram of impurity it is found that its molecular ion peak [M+H]+It is 296.009, i.e. the molecular weight of the impurity is
295.009, than ethyl demethylaminothiazolyloximate molecular weight more than 215.04 80.969, be tentatively inferred as acetyl bromide ethyl acetate with
The non-cyclization product of thiocarbamide reaction.Infer with reference to the issuable impurity of synthetic route and pertinent literature is reported, determine the impurity
Structure is as shown above.
By two mass spectrogram of Fig. 2 impurity it is found that ethyl demethylaminothiazolyloximate impurity of the present invention has the following structure formula：
By two mass spectrogram of impurity it is found that its molecular ion peak [M+H]+It is 202.02, i.e. the molecular weight of the impurity is
201.2, fewer than ethyl demethylaminothiazolyloximate molecular weight 215.04 13.84, tentatively it is inferred as in ethyl demethylaminothiazolyloximate
Hydrolysis of ester group product.Infer with reference to the issuable impurity of synthetic route and pertinent literature is reported, determine the impurity structure as above
It is shown.
Contamination levels product are used to analyze the purposes of cefotaxime raw material.
As a preferred technical solution, the separation side of impurity in ethyl demethylaminothiazolyloximate crude product of the present invention
Method specifically includes following steps：
(1) measure the ethyl demethylaminothiazolyloximate with LC-MS methods, according to the relative retention time of analyzed ingredient and/
Or molecular weight determines one or more impurity in the raw material；
(2) according to the relative retention time of one or more impurity described in step (1) and/or molecular weight
Chromatography retention behavior determines the separation condition of column chromatography；
(3) relative retention time and/or the corresponding one or more impurity of molecular weight are enriched with using reverse phase silica gel column.It is rich
Collect target impurity, further isolate and purify, collect the relative retention time and/or a kind of corresponding impurity of molecular weight.
The separation of impurity is all suitable in the ethyl demethylaminothiazolyloximate crude product that the present invention synthesizes any method.
For ethyl demethylaminothiazolyloximate, the document report for being directed to impurity is had no, using HPLC-MS (efficient liquid phases-matter
Compose LC-MS methods) structure derivation is carried out to the impurity in sample, but for small amount of impurity, LC-MS is difficult to be satisfied with
As a result.The present invention using reverse phase silica gel column in view of the above problems, be enriched with the relative retention time and/or the corresponding one kind of molecular weight
Or plurality of impurities.Target impurity is enriched with, is further isolated and purified, is collected the relative retention time and/or molecular weight is corresponding
A kind of impurity.This method is simple, and as a result accurately, the impurity analysis available for cephalo-type sample controls.
The invention has the advantages that：
(1) detection method is simple, result is accurate, is controlled suitable for the impurity analysis for analyzing cephalo-type sample.
(2) separation and concentration ethyl demethylaminothiazolyloximate impurity is used in combination with reverse phase silica gel column using LC-MS methods in the present invention,
The impurity rate of recovery reaches 5%~10%, and the purity of ethyl demethylaminothiazolyloximate is 96.5~98%.
(3) present invention LC-MS methods are combined with reverse phase silica gel post separation concentration method to ethyl demethylaminothiazolyloximate crude product into
The purposes of cefotaxime raw material is further analyzed in row detection and analysis according to contained contamination levels product.
Description of the drawings
Fig. 1 is the mass spectrogram of impurity one；
Fig. 2 is the mass spectrogram of impurity two.
Specific embodiment
The invention will be further described with reference to embodiments.
Embodiment 1
After sample is dissolved in methanol, wet method upper prop.Pillar first is rinsed with the ethyl acetate 300ml of relatively low polarity,
Again successively with pure methanol solution 100ml, 80% methanol-water solution 300ml of mass fraction, 60% methanol-water solution of mass fraction
300ml, 40% methanol-water solution 300ml of mass fraction and 20% methanol-water solution 300ml of mass fraction elutions；Each concentration
4 batches of receptions of gradient point, every batch of receive 50ml.Each gradient sample is laggard for 80% methanol through Rotary Evaporators extraction mass fraction
Row impurity enriched.Impurity analysis is carried out using LC-MS methods, chromatographic condition is as follows：1200 high performance liquid chromatographs of Agilent, color
Spectrum column type number is 150mm × 4.6 × 5um, and mobile phase is mass ratio 250:300:450 water-acetonitrile-methanol, mass fraction
0.1% potassium dihydrogen phosphate is buffer solution, is dissolved with methanol, sample size 20 μ l, flow velocity 1.5ml/min, Detection wavelength 245nm, column
25 DEG C of temperature, impurity detect appearance through UV detector.
Under the chromatographic condition, impurity one is about in 2.23min appearances, and impurity two is about in 1.18min appearances, interpretation of mass spectra
Using ESI positive ion detections, scanning range is 100~1000m/z, and the impurity rate of recovery is 5%, and purity is 99% after separation.
Embodiment 2
After sample is dissolved in methanol, wet method upper prop.Pillar first is rinsed with the ethyl acetate 300ml of relatively low polarity,
Again successively with pure methanol solution 100ml, 80% methanol-water solution 300ml of mass fraction, 60% methanol-water solution of mass fraction
300ml, 40% methanol-water solution 300ml of mass fraction and 20% methanol-water solution 300ml of mass fraction elutions；Each concentration
4 batches of receptions of gradient point, every batch of receive 50ml.Each gradient sample is laggard for 80% methanol through Rotary Evaporators extraction mass fraction
Row impurity enriched.Impurity analysis is carried out using LC-MS methods, chromatographic condition is as follows：1200 high performance liquid chromatographs of Agilent, color
Spectrum column type number is 150mm × 4.6 × 3.5um, and mobile phase is mass ratio 200:350:450 water-acetonitrile-methanol, mass fraction
0.4% potassium dihydrogen phosphate is buffer solution, is dissolved with methanol, sample size 20 μ l, flow velocity 1.5ml/min, Detection wavelength 245nm, column
25 DEG C of temperature, impurity detect appearance through UV detector.
Under the chromatographic condition, impurity one is about in 2.23min appearances, and impurity two is about in 1.18min appearances, interpretation of mass spectra
Using ESI positive ion detections, scanning range is 100~1000m/z, and the impurity rate of recovery is 7%, and purity is 99.5% after separation.
Embodiment 3
After sample is dissolved in methanol, wet method upper prop.Pillar first is rinsed with the ethyl acetate 300ml of relatively low polarity,
Again successively with pure methanol solution 100ml, 80% methanol-water solution 300ml of mass fraction, 60% methanol-water solution of mass fraction
300ml, 40% methanol-water solution 300ml of mass fraction and 20% methanol-water solution 300ml of mass fraction elutions；Each concentration
4 batches of receptions of gradient point, every batch of receive 50ml.Each gradient sample carries out after Rotary Evaporators produce 80% methanol of mass fraction
Impurity enriched.Impurity analysis is carried out using LC-MS methods, chromatographic condition is as follows：1200 high performance liquid chromatographs of Agilent, chromatography
Column type number is 150mm × 2.1 × 5um, and mobile phase is mass ratio 250:300:400 water-acetonitrile-methanol, is dissolved with methanol, into
Sample amount 20 μ l, flow velocity 1.5ml/min, Detection wavelength 245nm, 25 DEG C of column temperature, impurity detect appearance through UV detector.
Under the chromatographic condition, impurity one is about in 2.23min appearances, and impurity two is about in 1.18min appearances, interpretation of mass spectra
Using ESI positive ion detections, scanning range is 100~1000m/z, the impurity rate of recovery 10%, purity 99.5% after separation.
Claims (9)
1. a kind of separation method of impurity in ethyl demethylaminothiazolyloximate crude product, it is characterised in that：Specifically include following steps：
(1) ethyl demethylaminothiazolyloximate is measured with LC-MS methods, first ammonia thiophene is determined according to relative retention time and/or molecular weight
One or more impurity in hydroxyimino ethyl；
(2) one or more impurity corresponding with relative retention time and/or molecular weight are enriched with using reverse phase silica gel column, further
It isolates and purifies, collects the relative retention time and/or a kind of corresponding impurity of molecular weight.
2. the separation method of impurity in ethyl demethylaminothiazolyloximate crude product according to claim 1, it is characterised in that：LC-
Flowing phase pH value is 2.00~5.00 used by MS methods measure.
3. the separation method of impurity in ethyl demethylaminothiazolyloximate crude product according to claim 1, it is characterised in that：LC-
Mobile phase solvent is water-acetonitrile-methanol used by MS methods measure, and buffer solution is potassium dihydrogen phosphate.
4. the separation method of impurity in ethyl demethylaminothiazolyloximate crude product according to claim 3, it is characterised in that：Flowing
30%~60% acetonitrile, 0.1%~0.6% potassium dihydrogen phosphate, water 20%~25%, remaining as methanol are included in phase.
5. the separation method of impurity in ethyl demethylaminothiazolyloximate crude product according to claim 1, it is characterised in that：LC-
In the detection of MS methods the measuring conditions that use of HPLC for：Mobile phase solvent is water-acetonitrile-methanol mixed solution, and buffer solution is phosphoric acid
Potassium dihydrogen；Column temperature is 20-40 DEG C；Flow velocity is 1-1.5ml/min；Detection wavelength is 245~260；Chromatographic column is that stationary phase is ten
Eight alkyl silane bonded silica gels, 150 × 4.6 × 5um of model or 150mm × 4.6 × 3.5um or 150mm × 2.1 × 5um's
Stainless steel chromatographic column.
6. the separation method of impurity in ethyl demethylaminothiazolyloximate crude product according to claim 1, it is characterised in that：Mass spectrum
ESI positive ion detections are used in parsing；Scanning range is 100~3000m/z.
7. the separation method of impurity in ethyl demethylaminothiazolyloximate crude product according to claim 5, it is characterised in that：HPLC
The gradient elution step of chromatographic column is during measure：
(1) after sample is dissolved in methanol, wet method upper prop；
(2) first with the ethyl acetate 300ml of relatively low polarity rinse pillar, then successively with pure methanol solution 100ml, 80% methanol-
Aqueous solution 300ml, 60% methanol-water solution 300ml, 40% methanol-water solution 300ml and 20% methanol-water solution 300ml are washed
It is de-；Each 4 batches of receptions of concentration gradient point, every batch of receive 50ml；
(3) enrichment solution carries out HPLC detections.
8. the separation method of impurity in ethyl demethylaminothiazolyloximate crude product according to claim 1, it is characterised in that：It is described
Impurity has the following structure formula：
Molecular ion peak [M+H]+It is 296.009, the molecular weight of the impurity is 295.009, than ethyl demethylaminothiazolyloximate molecular weight
More than 215.04 80.969, the non-cyclization product reacted for acetyl bromide ethyl acetate with thiocarbamide.
9. the separation method of impurity in ethyl demethylaminothiazolyloximate crude product according to claim 1, it is characterised in that：It is described
Impurity has the following structure formula：
Molecular ion peak [M+H]+It is 202.02, i.e., the molecular weight of the impurity is 201.2, than ethyl demethylaminothiazolyloximate molecular weight
215.04 have lacked 13.84, are the hydrolysis of ester group product in ethyl demethylaminothiazolyloximate.
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